title: TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer.
abstract: Androgen receptor (AR) target genes direct development and survival of the prostate epithelial lineage, including prostate cancer (PCa). Thus, endocrine therapies that inhibit the AR ligand-binding domain (LBD) are effective in treating PCa. AR transcriptional reactivation is central to resistance, as evidenced by the efficacy of AR retargeting in castration-resistant PCa (CRPC) with next-generation endocrine therapies abiraterone and enzalutamide. However, resistance to abiraterone and enzalutamide limits this efficacy in most men, and PCa remains the second-leading cause of male cancer deaths. Here we show that AR gene rearrangements in CRPC tissues underlie a completely androgen-independent, yet AR-dependent, resistance mechanism. We discovered intragenic AR gene rearrangements in CRPC tissues, which we modeled using transcription activator-like effector nuclease (TALEN)-mediated genome engineering. This modeling revealed that these AR gene rearrangements blocked full-length AR synthesis, but promoted expression of truncated AR variant proteins lacking the AR ligand-binding domain. Furthermore, these AR variant proteins maintained the constitutive activity of the AR transcriptional program and a CRPC growth phenotype independent of full-length AR or androgens. These findings demonstrate that AR gene rearrangements are a unique resistance mechanism by which AR transcriptional activity can be uncoupled from endocrine regulation in CRPC.
authors.affiliation: Masonic Cancer Center, Graduate Program in Molecular, Cellular, and Developmental Biology and Genetics, and Biostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Nyquist
authors.forename: Yingming
authors.initials: Y
authors.lastname: Li
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Hwang
authors.forename: Luke S
authors.initials: LS
authors.lastname: Manlove
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Kevin A T
authors.initials: KA
authors.lastname: Silverstein
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Voytas
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dehm
mesh_terms: D000595:Amino Acid Sequence; D000736:Androstenes; D000737:Androstenols / Q000627:therapeutic use; D000818:Animals; D001483:Base Sequence; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D053263:Gene Regulatory Networks; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009570:Nitriles; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015202:Protein Engineering / Q000379:methods*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C410798:AR protein, human; D000736:Androstenes; D000737:Androstenols; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone